The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference and, for convenience, are referenced in the following text and respectively grouped in the appended bibliography.
Normal cell proliferation is regulated to a large degree by cyclin-dependent kinases (CDKs), which control cell cycle transitions through growth phases associated with DNA replication (S) and mitosis (M). Tumor cells exhibit mutations and can alter control mechanisms for passage through these transition points by a variety of mechanisms associated with the loss of normal cyclin-dependent kinase (CDK) activity. Evidence indicates that restoring CDK activity to normal catalytic activity levels can prevent tumor growth. The cyclin-dependent kinases play a critical role in cell cycle regulation. The sequential control of the various CDKs by cyclins allows for the proper progression through the cell cycle. In some tumors, increased levels of CDK proteins and cyclins are often found. Inhibitors of CDK may therefore be effective modulators of cell proliferation. Compound (1) ([4-amino-2-(1-methanesulfonylpiperidin-4-ylamino) pyrimidin-5-yl](2,3-difluoro-6methoxyphenyl)methanone) is known to be a potent and selective inhibitor of CDK4/Cyclin D1, CDK2/Cyclin E, and CDK1/Cyclin B.
Currently, there are no safe and effective marketed agents that act primarily to inhibit CDK or Cyclins. The sulfonate salt (primary amine) of compound (1) is currently being developed as an intravenous agent to inhibit CDK1. The method for preparing compound (1) and its use for the treatment for solid tumors are known1. Compound (1) can be prepared via dichloro-pyrimidine intermediate (4) which in turn is prepared by coupling 2-methoxy-5,6-difluorobenzaldehyde (2) and 5-bromo-2,4-dichloro-pyrimidine (3) as set out in Scheme 1.

2-Methoxy-5,6-difluorobenzaldehyde (2) is a key intermediate for the synthesis of compound (1) and other drug candidates. The synthetic route for preparing intermediate (2) has been disclosed2 and involves a low temperature (−78° C.) metalation/formylation of 3,4-difluoroanisole (5) as set out in Scheme 2.

The low temperature ortho-lithiation of halo-substituted aromatics method has safety issues because of the formation of the highly energetic and unstable benzyne intermediate3. On scale up, the rate of formation of this unstable intermediate increases substantially due to loss of cooling which can lead to a reaction runway, which may result in equipment damage and loss of containment. An uncontrolled charge of n-BuLi can also lead to a reaction runway. The benzyne intermediate anion3 in the halo-substituted aromatic reactions is known to be thermally unstable.
Accordingly, novel methods for stabilizing the reactions of low temperature lithiation of halogen-substituted aromatic compounds are required.